TETRAHEDRON

Tetrahedron 54 (1998) 4943-4948

Pergamon

Arylation of the Baylis-Hillman Adducts

Deevi Basavaiah* and Kannan Muthukumaran

School of Chemistry, Universityof Hyderabad,Hyderabad-500046, India

Received 8 October 1997; revised 3 March 1998; accepted 5 March 1998

Abstract : Palladium catalyzed a~latton of the Baylis-Hillman adducts, methyl 3-hydro~-2-

methylenealkanoates, has been described. © 1998 Elsevier Science Ltd. All rights reserved.

In recent years there has been much focus and emphasis on the Heck reaction for the construction of carbon-
carbon bond at the vinylic position involving palladium catalyzed coupling of haloarenes and haloalkenes with
alkenes, t-3 A variety of substituted and functionalized alkenes have been successfully arylated or alkenylated
via the Heck reaction to produce synthetically useful molecules. The Heck reaction i.e. arylation of allylic
alcohols has been well studied to provide arylated saturated carbonyl compounds or arylated allyl alcohols by
changing the reaction conditions. ~ Also the Heck reaction of ct, l~-unsaturated esters has been well
documented to produce arylated a, [~-unsaturated esters, z8 However the Heck reaction i.e. arylation of
alkenes possessing both allylic alcohol and ct, [3-unsaturated ester moieties in which carbon-carbon double
bond is an integral part of both aUyl alcohol and a, l~-unsaturated ester moieties, has not been studied. Such a
study is highly desirable and will be useful as this will further expand the scope of the Heck reaction in
synthetic organic chemistry. The Baylis-Hillman reaction provides an easy access for such interesting class of
alkenes having both allyi alcohol and ct, l~-unsaturated ester moieties. 9"ts As a part of our research program on
the Baylis-Hillman reaction, ts'n we herein report the Fleck reaction i.e. arylation of the Baylis-Hillman
adducts, methyl 3-hydroxy-2-methylenealkanoates (obtained via the DABCO catalyzed coupling of methyl
acrylate with aldehydes (Equation 1) ) under the influence of palladium acetate, thus providing a very simple
and convenient methodology for the synthesis of methyl 2-(arylmethyl)-3-oxoalkanoates, an important and
useful class ofsynthons.

We have first examined the reaction between methyl 3-hydroxy-2-methylene-3-phenyipropanoate (la) and
bromobenzene under the catalytic influence of palladium acetate. The best results were obtained when a

0040-.4020/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.

PII: S0040-4020(98 )00200-2
4944 D. Basavaiah, K. Muthukumaran/ Tetrahedron 54 (1998) 4943--4948

Rfl'.H + ~OMe DABCOy R ~ O M e

(eq. 1)

Table 1: Arylation of the Baylis-Hillman Adducts'

Substrate R Ar Time Product Yieldb

(h) (v,)

la Ph Ph 10 2c 81

la Ph 4-CH3C6I"I4 10 76

la Ph tx-Naphthyl 83

lb 4-i-C3HTC6I'-Lt Ph 10 5c 75

lb 4-i-C3H7C6I-I4 4-CH3C6I-h 10 6c 76

lb 4-i-C3HTC6H4 ~-Naphthyl 8 7c 82

1¢ 2-OCH3C6H4 Ph 18 8c 67

ld 4-CH3C~I4 Ph 12 9c 80

le 4-CICc,I'h Ph 8 10~ 60

If i-C3H7 Ph 10 ll d 61

If i-C3H7 4-CH3C6H4 12 d 76

lg n-CsHu Ph 13 d 64

lg n-CsHn cc-Naphthyl 14d 79

a) All reactionswere carriedout in lmM scale in TI-IFat reflux temperature for %18 h.
b) Yields of the productsobtained after columnchromatography ( using 5% EtOAcin hexane, silica gel ). The molecules 2. 3,
5-14 were obtainedas colorlessliquids and the molecule4 was obtainedas a colorlesssolid.
c) The molecules2, 5- 10 contain =5% impurityand were further purified by preparative HPLC(Shim-packPREP-ODScolumn.
methanol). All these compounds 2-10 gave satisfactoryIR, tH NIVlILt3C NMIL mass spectral and elemental analysis.
d) tH NMR and 13CN M spectra showthat these moleculescontain =5-8% impurity.

solution of methyl 3-hydroxy-2-methylene-3-phenylpropanoate (la) (1 mM) and bromobenzene (2 mM) in

THF (3 mL) was refluxed for 10h in the presence of Pd(OAc)2 (2 tool%), NaHCO3 (2.5 raM) and n-Bu4NBr (1
mM), thus providing methyl 2-benzyi-3-oxo-3-phenylpropanoate (2) after column chromatography (5%
 D. Basavaiah, K. Muthukumaran/ Tetrahedron 54 (1998) 4943-4948 4945

EtOAc in hexane, silica gel) in 81% yield. This molecule is contaminated with ~.5% impurity. However
purification by preparative I-IPLC (Shim-pack PREP-ODS column using methanol as solvent) provided the
pure methyl 2-benzyl-3-oxo-3-phenyipropanoate (2).
Encouraged by this result we have subjected a variety of the Baylis-Hillman adducts to arylation using
various aryl bromides which produced the desired methyl 2-(aryimethyl)-3-oxoalkanoates (Table 1,
Equation 2).

Pd(OAc)2(cat), n-Bu4NBr R OMe

R OMe + Ar-Br NaHCO3, THF, reflux v (eq.2)
60-83% Ar
la-lg 2-14

In conclusion, the arylation of the Baylis-Hillman adducts, methyl 3-hydroxy-2-methylenealkanoates, provides

an easy access to methyl 2-(arylmethyl)-3-oxoalkanoates, an important class of organic synthons, thus
highlighting the importance and applications of both the Heck and Baylis-Hillman reactions.

Acknowledgments: We thank DST (New Delhi) for funding this project. KMK thanks UGC (New Delhi) for
his research fellowship. We also thank UGC (New Delhi) for COSIST and Special Assistance Programs in
Organic Synthesis in the School of Chemistry, University of Hyderabad.

EXPERIMENTAL

The melting points were recorded on Superfit melting point apparatus and are uncorrected. IR spectra were
recorded on Jasco-FT-IR model 5300 spectrometer using samples as neat liquid or solution in CH2CIr ~H
NMR (200 MHz) and 13C NMR (50 MHz) spectra were recorded on Bruker-AC-200 spectrometer using
chloroform-d as solvent and tetramethylsilane (TMS, 8 = 0 ppm) as internal standard. Mass spectra were reco-
rded on micromass VG 7070H instrument. Elemental analyses were performed on Perkin-Elmer 240C-CHN
analyser. I-IPLC analyses were performed on Shimadzu LC-10AD instrument equipped with SPD-10A UV-
VIS detector using Shim-pack PREP-ODS column and methanol as solvent.

General Procedure for the preparation of methyl 2-arylmethyi-3-oxo-alkanoates (2-14):

A solution of methyl 3-hydroxy-2-methylenealkanoate (1) (1 raM) and aryl bromide (2 mM) in TI-IF (3mL)
was refluxed for 7-18 hours (as mentioned in the Table 1) in the presence of Pd(OAc)2(2 tool%, 0.02 raM, 4.5
mg), NaI-ICO3 (2.5 raM, 210 nag) and n-Bu,NBr (1 raM, 322 mg). Then the reaction mixture was cooled,
diluted with water and extracted with ether. The organic layer was dried over anhydrous NazSO4 and solvent
4946 D. Basavaiah, K. Muthukumaran / Tetrahedron 54 (1998) 4943--4948

was evaporated. The crude product obtained was purified by column chromatography (5% EtOAc in hexane,
silica gel). The molecules 2, 5-11 contain ~5% impurities and were further purified by preparative I-IPLC
(Shim-pack PREP-ODS column) using methanol as solvent. The compounds 12-14 contain ~5-8% impurities
as indicated by tH NMR and ~3C NMR spectral analysis. Attempts to further purification of the molecules 12-
14 by preparative HPLC were not successful.

Methyl 2-benzyl-3-oxo-3-phenylpropanoate (2):

Yield: 81%; IR (neat) vmax/cm'~: 1685, 1741; ~H NMR:/5 3.33 (d, 2H, J= 7.0 Hz), 3.63 (s, 3I-I), 4.64 (t, 1H,
J= 7.0 Hz), 7.1 I-7.62 (m, 8H), 7.89-8.05 (m, 2I-1); ~3C NMR:/5 34.83, 52.40, 55.82, 126.61, 128.50, 128.59,
128.68, 128.82, 133.51, 136.13, 138.32, 169.66, 194.39; MS (m/z): 268 (M+); Analysis calculated for
C17H1603: C, 76.09; H, 6.01; found: C, 76.15; H, 6.03.

Methyl 2-(4-methylphenyl)methyl-3-oxo-3-phenyipropanoate(3):
Yield: 76%; IR (neat) vmax/cmq: 1687, 1741; IH NMR: 6 2.27 (s, 3H), 3.28 (d, 2FL J= 7.0 Hz), 3.62 (s,
3H), 4.61 (t, 1H, J= 7.0 Hz), 7.01-7.63 (m, 7H), 7.94 (d, 2I-I, J= 7.2 Hz); ~3C NMR:/5 20.97, 34.46, 52.43,
56.04, 128.72, 129.23, 133.52, 135.28, 136.15, 169.77, 194.47; MS (m/z): 282 (M*); Analysis calculated for
CnHnO3: C, 76.57; FL 6.42; found: C, 76.36; H, 6.45.

Methyl 2-(naphth-l-ylmethyl)-3-oxo-3-phenyipropanoate (4):

Yield: 83%; M. P: 68-70°C; IR (CH2CI2) vmax/cm'~: 1676, 1738; IH NMR:/5 3.63 (s, 3H), 3.82 (d, 2H, J=
6.8 Hz), 4.83 (t, 1H, J= 6.8 Hz), 7.17- 8.19 (m, 12H); ~3C NMR: 6 31.81, 52.50, 54.59, 123.16, 125.41,
125.59, 126.27, 127.25, 127.53, 128.53, 128.61, 129.00, 131.63, 133.47, 133.93, 134.14, 136.26, 169.88,
194.54; MS (m/z): 318 (M+); Analysis calculated for C2tHnO3: C, 79.22; H, 5.69; found: C, 79.26; H, 5.67.

Methyl 2-benzyi-3-(4-(1-methylethyl)phenyl)-3-oxopropanoate(5):
Yield: 75%; IR (neat) vmax/cma: 1682, 1741; ~H NMR: 8 1.24 (d, 6II, J= 6.8 Hz), 2.92 (sept, IH, J=6.8 I--Iz),
3.32 (m, 2H), 3.63 (s, 3H), 4.63 (t, 1H, J= 7.2 Hz), 7.12- 7.35 (m, 7H), 7.89 (d, 2I-I, J= 8.4 I-Iz); 13CNMR:8
23.61, 34.31, 34.95, 52.50, 55.93, 126.66, 126.91, 128.58, 128.94, 129.02, 134.07, 138.62, 155.26, 169.91,
193.93; MS (m/z): 310 (M+); Analysiscalculated for C20H2203:C, 77.39; H, 7.14; found: C, 77.45; I4, 7.18.

Methyl 2-(4-methylphenyl)methyl-3-(4-(l-methylethyl)phenyl)-3-oxopropanoate(6):
Yield:76%; IR (neat) vmax/cm't: 1682, 1741; tH NMR:8 1.25 (d, 6H, J=6.8 Hz), 2.28 (s, 3I-I), 2.93 (sept, 1H,
J=6.8 Hz), 3.28 (m, 2H), 3.64 (s, 3H), 4.60 (t, 1H, J=7.0 Hz), 7.01-7.39 (ra, 6I-I), 7.89 (d, 21-I, J=8 I-Iz); ~3C
NMR:6 21.03, 23.62, 34.31, 34.54, 52.48, 56.09, 126.90, 128.79, 129.03, 129.27, 134.08, 135.53, 136.16,
155.23, 169.98, 194.00; MS (m/z): 324 (M+); Analysis calculated for C2~H2403:C, 77.75; H, 7.45; found: C,
 D. Basavaiah, K. Muthukumaran / Tetrahedron 54 (1998) 4943-4948 4947

77.65; H, 7.42.

Methyl 3-(4-(l-methylethyl)phenyl)-2-(naphth-l-ylmethyl)-3-oxopropanoate (7):

Yield: 82%; IR (neat) vmax/cm't: 1682, 1739; tH NMR: 5 1.22 (d, 6H, J= 7.0 Hz), 2.91 (m, IH), 3.63 (s,
3H), 3.80 (d, 2H, J= 7.2 Hz), 4.81 (t, IH, J= 7.2 Hz), 7.15- 8.08 (m, llH); ~3C NMR: fi 23.57, 31.90, 34.28,
52.51, 54.71, 123.33, 125.51, 125.63, 126.29, 126.82, 127.33, 127.55, 128.95, 129.05, 131.81, 134.08,
134.30, 134.44, 155.18, 170.10, 194.09; MS (m/z): 360 (M+); Analysis calculated for C24/-I2403:C, 79.97; H,
6.71; found: C, 80.21; H, 6.68.

Methyl 2-benzyl-3-(2-methoxyphenyl)-3-oxopropanoate (8):

Yield: 67%; IR (neat) vmax/cm'~: 1672, 1739; ~H NMR: 8 3.27 (m, 2H), 3.64 (s, 3H), 3.85 (s, 31-I),4.67 (t,
If-I,J= 6.8 Hz), 6.85- 7.70 (m, 9H); X3C NMR: 8 34.61, 52.02, 55.24, 60.10, I I 1.49, 120.86, 126.32, 126.90,
128.28, 128.88, 131.04, 134.17, 138.99, 158.31, 170.41, 196.03; MS (m/z): 298 (M'); Analysiscalculateclfor
CnHlsO4: C, 72.47; H, 6.08; found: C, 72.24; H, 6.10.

Methyl 2-benzyl-3-(4-methylphenyl)-3-oxopropanoate (9):

Yield: 80%; IR (neat) vmax/cm'~: 1682, 1741; IH NMR: 8 2.39 (s, 3H), 3.31 (m, 2H), 3.62 (s, 3H), 4.62 (t,
IH, J= 7.2 .Hz), 7.15- 7.30 (m, 7H), 7.85 (d, 2H, J= 8 Hz); t3C NMR: ~ 21.60, 34.89, 52.41, 55.80, 126.61,
128.52, 128.82, 128.85, 129.43, 133.72, 138.51, 144.52, 169.83, 193.95; MS (m/z): 282 (M+); Analysis
calculated for CisHnO3: C, 76.57; H, 6.42; found: C, 76.65; H, 6.39.

Methyl 2-benzyl-3-(4-chiorophenyl)-3-oxopropanoate (10):

Yield: 60%; IR (neat) vmax/cm't: 1687, 1741; ~H NMR: 5 3.32 (d, 2H, J=7.2 Hz), 3.64 (s, 3H), 4.58 (t, 1H,
J= 7.6 Hz ), 7.16- 7.47 (m, 7H), 7.86 (m, 2H); ~3C NMR: 6 34.80, 52.53, 55.88, 126.73, 128.57, 128.83,
129. 02, 130.02, 134.56, 138.15, 140.07, 169.41, 193.24; MS (m/z): 302 (M+); Analysis calculated for
CtTHtsO3Cl: C, 67.44; H, 4.99; found: C, 67.3 I; H, 5.01.

Methyl 2-benzyl-4-methyl-3-oxopentanoate(II):
Yield: 61%; IR (neat) vmax/cm't: 1714, 1743; tH NMR: 5 0.86 (d, 31-I,J--6.8Hz), 1.04 (d, 3H, J= 6.8 Hz),
2.60 (m, IH), 3.15 (d, 2H, J= 7.4 Hz), 3.68 (s, 3H), 3.95 (L If-I,J= 7.4 Hz), 7.05- 7.36 (m, 5H); t3C NMR: 8
17.67, 17.76, 34.51, 41.33, 52.34, 58.54, 126.67, 128.55, 128.92, 138.42, 169.54, 208.29.

Methyl 2-(4-methylphenyl)methyi-4.methyl-3-oxopentanoate (12):

Yield: 76%; IR (neat) vmax/cm'i: 1714, 1745; IH NMR: ~ 0.89 (d, 3H, J=6.8 Hz), 1.05 (d, 3H, J= 6.8 Hz),
2.29 (s, 3H), 2.60 (m, liT), 3.11 (d, 2FL J=7.2 Hz), 3.68 (s, 3H), 3.93 (t, lI-I, J= 7.2 Hz), 7.05 (m, 4H); ~3C
NMR: 6 17.65, 17.73, 20.94, 34.06, 41.25, 52.25, 58.57, 128.70, 129.16, 135.21, 136.09, 169.55, 208.37.
4948 D. Basavaiah, K. Muthukumaran/ Tetrahedron 54 (1998) 4943-4948

Methyl 2-benzyl-3-oxooctanoate (13):

Yield: 64%; IR (neat)vmax/cm'~: 1716, 1743; ~H NMR: 5 0.83 (t, 3H, J=6.8 Hz), 1.05-1.62 (m, 6H), 2.18-
2.61 (m, 2H), 3.15 (d, 2H, J=7.6 Hz), 3.68 (s, 3H), 3.80 (t, 1H, J= 7.6 Hz), 7.05- 7.36 (m, 5H); ~3CNMR: ~i
13.74, 22.26, 22.89, 30.99, 34.10, 42.75, 52.21, 60.30, 126.57, 128.48, 128.72, 138.22, 169.51,204.54.

Methyl 2-(naphth-l-ylmethyl)-3-oxooctanoate (14):

Yield: 79%; IR (neat) vmax]cm'l: 1716, 1745; ~H NMR: 5 0.82 (t, 3H, J= 6.6 Hz), 1.00-1.55 (m, 6H), 2.10-
2.58 (m, 2H), 3.67 (m, 5H), 4.00 (t, IH, J= 7.6 Hz), 7.25- 8.05 (m, 7H); 13C NMR: 6 13.78, 22.29, 22.90,
30.99, 31.20, 43.02, 52.37, 59.06, 123.16, 125.44, 125.64, 126.27, 127.26, 127.56, 129.01, 131.50, 133.96,
134.10, 169.79, 204.83.

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